tbuckley/cabot-search huggingface dataset:
Abstract 6102: Single-cell RNA sequencing of lung adenocarcinoma patients reveals age-dependent tumour microenvironment alterations that facilitate response to immunotherapy
Authors: Xiaoqiang Zhu, Hai Wang, Xuefeng Pan, Jie Hong, Jason Wing Hon Wong, Haoyan Chen, Youwei Zhang
Journal: Cancer Research (2022)

Abstract Background: Immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD). While the increase in cancer incidence with age and age-associated changes in immune function have been well characterized, age-related differences in the intratumoral immune populations and how this affects immunotherapy response remain unknown. Methods: We collected clinical data from 3,544 samples treated with immune checkpoint blockade (ICB) at the pan-cancer level. Single-cell RNA sequencing data from 19 LUAD samples were integrated and analyzed. Cell types were identified based on canonical marker gene expression. Results: Aged individuals responded more efficiently to ICB treatment at the pan-cancer level. By focusing on LUAD, we showed that patients aged above 46 responded better and had longer progression-free survival than younger counterparts. Further, we presented a 58,031-cell catalog of age-associated single-cell transcriptomes from LUAD patients. Our analysis revealed the accumulation of immune response and chronic inflammation with increasing age. Aged tissues (&amp;gt; 60 years) displayed dominant exhausted natural killer (NK)/T cells and T regulatory cells and were enriched with two subtypes of tumour-associated macrophages marked by SPP1 and CX3CR1 expression, respectively. Furthermore, the ageing dynamics of stroma cells created a pro-tumor microenvironment reflected by increased angiogenesis and collagen formation. Conclusions: These results revealed an increasing immune-suppressive tumour microenvironment with age, supporting an observation of improved ICB response in older LUAD patients. Our extensive single-cell analysis enhances the understanding of age-dependent molecular and cellular dynamics in LUAD. Our results highlight the importance of considering age as a factor for ICB response and provide a rich resource for developing therapeutic targets in LUAD-microenvironment interactions. Citation Format: Xiaoqiang Zhu, Hai Wang, Xuefeng Pan, Jie Hong, Jason Wing Hon Wong, Haoyan Chen, Youwei Zhang. Single-cell RNA sequencing of lung adenocarcinoma patients reveals age-dependent tumour microenvironment alterations that facilitate response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6102.
Abstract 5698: Genome-wide DNA methylation profiling for differentiating synchronous endometrial and ovarian cancer
Authors: Yusanne Yung Sing Chan, Oscar Gee Wan Wong, Annie Nga Yin Cheung
Journal: Cancer Research (2022)

Abstract Background: Synchronous endometrial and ovarian cancer (SEOC) refers to simultaneously discovered endometrial and ovarian tumours on the same patient. SEOC may represent double primary (DP) tumours that arise independently on the two sites, or clonally related (CR) tumours that arise either on the endometrium or ovary and metastasized to the other site. Accurate differential diagnosis between these two scenarios can implicate on the treatment options and prognostication of SEOC. However, it is difficult to achieve as the histopathological features of DP and CR tumours are often ambiguous. DNA methylation landscape of SEOC may provide markers for differentiating DP and CR tumours but remain largely unexplored. Methods: The archival tissues of six pairs of SEOC and their accompanied normal uterine tissues were retrieved. The tumours were accessed by conventional histopathological criteria and mitochondrial DNA (mtDNA) sequencing to categorize them into DP or CR. We then analyzed the methylation profiles of &amp;gt;850,000 CpG sites of the tumor samples using the Illumina Infinium MethylationEPIC BeadChip array. Downstream methylation analysis was performed in the R/Bioconductor package ChAMP. Gene ontology (GO) enrichment analysis on the methylation driven genes was done using PANTHER. Results: mtDNA sequencing revealed that among the 6 cases of SEOC, there are 3 DP and 3 CR. Clustering analysis of differentially methylated CpGs (DMPs) between tumours of the same tissue type effectively distinguished endometrial and ovarian tumours into DP or CR. Thus, DP and CR endometrial tumour showed 50 DMPs and 15 differentially methylated regions (DMRs), but no significantly enriched signaling pathway was identified. On the other hand, there were 1,105 DMPs and 44 DMRs that mapped to 601 known genes between DP and CR ovarian tumours. GO analysis revealed that the hypomethylated genes in CR ovarian tumour were enriched in several metastatic-related processes, including cellular response to stimulus, regulation of cell projection organisation, cell migration and negative regulation of voltage-gated potassium channel activity. Conclusions: Taken together, our findings demonstrated that DNA methylation profiling can be used for SEOC patient stratification and may enhance our understanding of epigenetic regulation of SEOC pathogenesis. Citation Format: Yusanne Yung Sing Chan, Oscar Gee Wan Wong, Annie Nga Yin Cheung. Genome-wide DNA methylation profiling for differentiating synchronous endometrial and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5698.
Abstract 3130: IL-27 signaling regulates anti-cancer immune response in hepatocellular carcinoma
Authors: Aleksandra M. Mazitova, Turan Aghayev, Jennifer Fang, Amiran Dzutsev, Giorgio Trinchieri, Kerry S. Campbell, Sergei I. Grivennikov, Ekaterina K. Koltsova
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor survival and limited therapeutic options. HCC development is accompanied by underlying chronic inflammation, which represents a major unifying mechanism for tumor promotion. While some tumor-promoting inflammatory mechanisms had been proposed, the identity of immune mechanisms controlling anti-cancer immunity in HCC remain poorly understood. Interleukin (IL)-27 receptor signaling plays an anti-inflammatory role in a variety of infectious and chronic inflammatory diseases. Here, using genetic and pharmacological approaches we found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. Genetic loss of IL-27R suppressed HCC in both carcinogen-induced and non-alcoholic steatohepatitis (NASH)-driven models. Mechanistically, the pro-tumorigenic effect was mediated by an immunoregulatory role of IL-27R within the tumor microenvironment, particularly the suppression of cytotoxic Natural killer (NK) cells. Single-cell RNA analysis further established the role of IL-27R signaling in restraining cytotoxic populations of NK cells. IL-27R ablation enhanced the accumulation and activation of cytotoxic NK cells during acute liver injury and in HCC tumors, while depletion or functional impairment of NK cells abrogated the effect of genetic IL-27R disruption. Taken together, our data suggest an unexpected role of IL-27R signaling as a novel immunological checkpoint regulating innate cytotoxic cell activity and promoting development of HCC of different etiologies. Citation Format: Aleksandra M. Mazitova, Turan Aghayev, Jennifer Fang, Amiran Dzutsev, Giorgio Trinchieri, Kerry S. Campbell, Sergei I. Grivennikov, Ekaterina K. Koltsova. IL-27 signaling regulates anti-cancer immune response in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3130.
Phase I Trial of a Novel Anti-HER2 Antibody–Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer
Authors: Jian Zhang, Dongmei Ji, Weina Shen, Qin Xiao, Yajia Gu, Joyce O'Shaughnessy, Xichun Hu
Journal: Clinical Cancer Research (2022)

ARX788 is a novel antibody-drug conjugate (ADC) comprised of an anti-HER2 monoclonal antibody and a potent tubulin inhibitor payload AS269 that is site-specifically conjugated to the antibody via a non-natural amino acid incorporated into the antibody. Herein, we present the results of a phase I study of the safety, pharmacokinetics, and antitumor activity of ARX788 in HER2-positive metastatic breast cancer (MBC) patients.Patients with HER2-positive MBC received ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, or 1.5 mg/kg Q3W, or 0.88, 1.1, or 1.3 mg/kg Q4W. The dose-limiting toxicity (DLT) was assessed for 84 days for pulmonary toxicity and at a duration of one cycle (21 or 28 days) for other toxicities.In total, 69 patients were enrolled. No DLT or drug-related deaths occurred. Most patients (67/69; 97.1%) experienced at least one treatment-related adverse event (TRAE). Common ({greater than or equal to} 30%) TRAEs included an increase in aspartate aminotransferase, an increase in alanine aminotransferase, corneal epitheliopathy, alopecia, hypokalemia, interstitial lung disease (ILD)/pneumonitis, and an increase in aldosterone. While 34.8% of participants experienced ILD/pneumonitis, only two had a severity of grade 3. At 1.5 mg/kg Q3W, the recommended phase II dose, the objective response rate was 65.5% (19/29, 95% confidence interval [CI], 45.7-82.1), the disease control rate was 100% (95% CI, 81.2-100), and the median progression-free survival was 17.02 months (95% CI, 10.09 to not reached).ARX788 demonstrated a manageable safety profile with promising preliminary signs of activity in HER2-positive MBC patients who progressed on prior anti-HER2 therapies.
Abstract 3331: Effective multitargeted kinase inhibitors for metastatic castration-resistant prostate cancer predicted by integrative systems-based modeling
Authors: Thomas Bello, Claudia Paindelli, Luis Diaz-Gomez, Antonios Mikos, Peter Nelson, Taranjit Gujral, Eleonora Dondossola
Journal: Cancer Research (2022)

Abstract Metastatic castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer (PCa) with limited therapeutic opportunities. Here, we applied an unbiased systems-based modeling approach called Kinome Regularization (KiR) to identify candidate kinase inhibitors (KIs) for the treatment of CRPC. KiR is a method of target deconvolution that harnesses the polypharmacology of KIs to identify critical kinases involved in a specific cellular activity (i.e., cell proliferation). By computationally integrating the results of a functional drug screen with prior biochemical knowledge, we generated KiR models for a panel of PCa cell lines that predict KIs effective at abrogating CRPC cell growth and proliferation. Two predicted KIs (PP121 and SC-1) showed significant inhibition of PCa cell growth and kinase-mediated growth factor signaling in vitro and in primary subcutaneous tumors. However, therapy resistance emerged in bone metastases, as identified by analysis in a 3D in vitro engineered bone mimetic environment and in tumors implanted in mouse bones. A combination of PP121 and SC-1 with standard-of-care chemotherapy overcame the resistance, enhancing both tumor response and mouse survival. These results suggest that combining multi-targeted KIs with chemotherapy may represent an effective strategy for CRPC treatment. Overall, our findings demonstrate the application of a multidisciplinary strategy that blends bench science with machine-learning approaches for rapidly identifying KIs that result in desired phenotypic effects. Citation Format: Thomas Bello, Claudia Paindelli, Luis Diaz-Gomez, Antonios Mikos, Peter Nelson, Taranjit Gujral, Eleonora Dondossola. Effective multitargeted kinase inhibitors for metastatic castration-resistant prostate cancer predicted by integrative systems-based modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3331.
Abstract 1196: Elucidating compound mechanism of action and polypharmacology with a large-scale perturbational profile compendium
Authors: Lucas Zhongming Hu, Eugene Douglass, Ron Realubit, Charles Karan, Mariano Alvarez, Andrea Califano
Journal: Cancer Research (2022)

Abstract Traditional approaches to elucidate small molecule mechanism of action (MoA) are usually based on affinity binding assays. These often fail to detect lower affinity binding targets and secondary effectors that are usually highly tissue context-dependent. As such, these can vary dramatically across different cancer types. To address this challenge and facilitate more quantitative approaches to targeted cancer therapy, a more comprehensive picture of drug MoA, including poly-pharmacology and toxicity effects mediated by the full range of its high-affinity (primary), as well as its context-specific lower-affinity (secondary) and downstream effector (tertiary) targets. For this purpose, we generated transcriptional genome-wide RNA-Seq profiles of cancer cell lines, following compounds perturbation with FDA approved and late-stage experimental oncology drugs using a fully automated and highly efficient PLATE-Seq technology1. Compared to prior approaches, this provides (a) genome-wide readouts, rather than readouts limited to a small set of landmark genes, (b) in cell lines that were specifically selected as the highest-fidelity models for published human cancer cohorts, using the OncoMatch algorithm2, and (c) for a drug repertoire that is clinically relevant. In addition, to avoid confounding effects from drug stress/death response pathway activation—a common issue in previous studies—drugs were titrated at their maximum sub-lethal concentration (48-hr IC20) using 10-point dose response curves in each cell line. The ~20,000 molecular profiles generated by these assays were analyzed using the VIPER algorithm3 to reproducibly assess the effect of each drug on the activity of ~6,500 regulatory and signaling proteins compared to vehicle control. The resulting PanACEA (Pancancer Activity-based Compound Efficacy Analysis), a database comprising drug perturbation profiles for 23 different cancer cell lines and &amp;gt; 700 oncology drugs, representing the largest resources of functionally annotated, genome-wide perturbational profiles for clinically relevant drugs. Systematic analysis identified critical drug mechanism of action and drugs capable of reproducibly targeting undruggable proteins, such as MYC or KRAS. We also leveraged graph theory-based network approach to generate a conserved drug functional network and drug functional networks in different cancer contexts, which pinpoint critical novel poly-pharmacology effects. Citation Format: Lucas Zhongming Hu, Eugene Douglass, Ron Realubit, Charles Karan, Mariano Alvarez, Andrea Califano. Elucidating compound mechanism of action and polypharmacology with a large-scale perturbational profile compendium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1196.
Abstract 5318: Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study
Authors: Lynn Jackson Howie, Ezra M. Chung, Young-Seung Kim, Yujin Jung, Hyunjin Jung, Stephen Yoo
Journal: Cancer Research (2022)

Abstract Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1 and may represent a promising therapeutic target for tumors that are anti-PD-1/PD-L1 antibody refractory. BTN1A1 was identified as a potential stress-inducible candidate immune checkpoint using the STCube in vivo immune target discovery platform. Additional analyses revealed that BTN1A1 was highly expressed in multiple human tumor types including urothelial carcinoma and NSCLC, with no overlap between BTN1A1 and PD-1/PDL-1 expression patterns. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. A humanized anti-BTN1A1 antibody, hSTC810, was developed and found to suppress tumor growth in A549 CDX humanized murine models. Further studies identified Galectin 9 (Gal9) as a BTN1A1 receptor that can form a three protein complex with BTN1A1 and PD-1, thereby suppressing T cell receptor signaling and T cell activation. As high Gal9 expression levels are correlated with poor prognosis in multiple cancers, our results highlight this BTN1A1-Gal9-PD-1 axis as a novel therapeutic target for immunotherapeutic drug development. Given these findings, a first in human study of hSTC810 is in development to evaluate the safety profile of this therapy and to identify a dose for its further evaluation as an anticancer therapy. PK modeling including allometric scaling was performed to conduct simulations to predict the PK profile of hSTC810 after IV administration in humans and to identify possible doses needed to achieve tumor concentrations corresponding to the minimum anticipated biological effect level (MABEL) of 20% receptor occupancy (RO), 80% RO, or 95% RO. The partition coefficient was used to predict concentrations at the tumor site based on predicted serum concentrations. Simulations were performed for 100 subjects after the administration of multiple Q2W doses. The dose of 0.1 mg/kg was predicted to have &amp;lt;20% RO, 0.3 mg/kg to have ~21-35% RO, 1 mg/kg to have ~47-65% RO and 15 mg/kg to have ~93-96% RO at steady state. We anticipate beginning study enrollment in the first quarter of 2022 at sites in the United States sand South Korea. The study is a standard 3+3 dose-escalation with a dose of 0.3 mg/kg for a single patient followed by a starting dose of 1 mg/kg. Citation Format: Lynn Jackson Howie, Ezra M. Chung, Young-Seung Kim, Yujin Jung, Hyunjin Jung, Stephen Yoo. Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5318.
Abstract 5499: Efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE)
Authors: Kun Qian, Bin Hu, Ming He, Zi-Tong Wang, Yu Liu, Hua-Gang Liang, Zhi-Yong Su, Yu-Shang Cui, Li-Jun Liu, Yi Zhang
Journal: Cancer Research (2022)

Abstract Background: Currently, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been proved to significantly improve the clinical outcome of patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Icotinib is an oral, reversible and selective first-generation EGFR-TKI. The survival benefits of 1-year and 2-year adjuvant icotinib in patients with EGFR-mutant NSCLC have been confirmed in previous studies. However, the optimal duration of adjuvant icotinib remains unknown. This study (ICAPE) evaluated the efficacy of 1.5-year adjuvant therapy with icotinib for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Methods: Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. Primary endpoint was disease-free survival (DFS). Secondary endpoints included 1-year, 3-year, as well as 5-year OS rates, and the DFS according to the BIM mutation status (mutant-type and wild-type) and EGFR mutation types (19 del and 21 L858R). Results: Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p=0.75) and no significant difference was found in the median DFS according to EGFR mutation types (all p&amp;gt;0.05). Conclusions: The phase II ICAPE study demonstrated that 1.5-year adjuvant therapy with icotinib had a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma with a long median DFS and high 5-year OS rates which is consistent with other icotinib’s study. Icotinib is suggested to be used as an adjuvant therapy option in IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Citation Format: Kun Qian, Bin Hu, Ming He, Zi-Tong Wang, Yu Liu, Hua-Gang Liang, Zhi-Yong Su, Yu-Shang Cui, Li-Jun Liu, Yi Zhang. Efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5499.